The FDA has approved the use of several 2′,3′-dideoxynucleosides (ddNs) and 2′,3′-didehydro-2′,3′-dideoxynucleosides (d4Ns) in anti-HIV drugs. These compounds are important antiviral compounds, which terminate viral DNA polymerization after their incorporation by reverse transcriptase. Specifically, the FDA has approved the use of 2′,3′-dideoxycytidine (ddC); 2′,3′-didehydro-3′-deoxythymidine (d4T, Stavudine); 3′-azido-3′-deoxythymidine (AZT); 2′,3′-dideoxyinosine (ddI); β-3′-deoxy-3′-thiocytidine (3TC); Abacavir (ABC); and Emtricitabine in anti-HIV therapeutics.
Currently, d4Ns can be synthesized using several popular methods. For example, these methods include the Corey-Winter reaction through cyclic thionocarbonates, the Eastwood olefination through cyclic orthoformates, the Mattocks reaction through bromoacetates, and olefin metathesis via a ring closure reaction. In addition, 2′,3′-anhydro-2′-deoxy-uridine and -thymidine can be converted to d4Ns via base-catalyzed elimination. Furthermore, d4Ns may also be synthesized via oxidative elimination of nucleoside α-phenyl-selenoxides and via substitution of nucleoside dimesylates by selenide and telluride dianions. In some cases, these methods can be expensive, can vary in complexity and ease, and can undesirably increase the cost of disease treatment.
Therefore, there exists a need for new synthetic methods of d4Ns which can provide additional options for preparing d4Ns. There is also a need for additional synthetic methods that have the potential of reducing the costs of disease treatment as well as novel analog/drug discovery.